Abstract
Chimeric RNAs originating from two or more different genes are known to exist not only in cancer, but also in normal tissues, where they can play a role in human evolution. However, the exact mechanism of their formation is unknown. Here, we use RNA sequencing data from 462 healthy individuals representing 5 human populations to systematically identify and in depth characterize 81 RNA tandem chimeric transcripts, 13 of which are novel. We observe that 6 out of these 81 chimeras have been regarded as cancer-specific. Moreover, we show that a prevalence of long introns at the fusion breakpoint is associated with the chimeric transcripts formation. We also find that tandem RNA chimeras have lower abundances as compared to their partner genes. Finally, by combining our results with genomic data from the same individuals we uncover intronic genetic variants associated with the chimeric RNA formation. Taken together our findings provide an important insight into the chimeric transcripts formation and open new avenues of research into the role of intronic genetic variants in post-transcriptional processing events. © 2014 Greger et al.

Abstract
Identification of genetic variants affecting splicing in RNA sequencing population studies is still in its infancy. Splicing phenotype is more complex than gene expression and ought to be treated as a multivariate phenotype to be recapitulated completely. Here we represent the splicing pattern of a gene as the distribution of the relative abundances of a geneâ(tm) s alternative transcript isoforms. We develop a statistical framework that uses a distance-based approach to compute the variability of splicing ratios across observations, and a non-parametric analogue to multivariate analysis of variance. We implement this approach in the R package sQTLseekeR and use it to analyze RNA-Seq data from the Geuvadis project in 465 individuals. We identify hundreds of single nucleotide polymorphisms (SNPs) as splicing QTLs (sQTLs), including some falling in genome-wide association study SNPs. By developing the appropriate metrics, we show that sQTLseekeR compares favorably with existing methods that rely on univariate approaches, predicting variants that behave as expected from mutations affecting splicing. © 2014 Macmillan Publishers Limited.

Abstract
Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes-most of which are not differentially expressed-exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV ) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences. © 2014 Hansen et al.

Abstract
In the last decades propofol became established as an intravenous agent for the induction and maintenance of both sedation and general anesthesia procedures. In order to achieve the desired clinical effects appropriate infusion rate strategies must be designed. Moreover, it is important to avoid or minimize associated side effects namely adverse cardiorespiratory effects and delayed recovery. Nowadays, to attain these purposes the continuous propofol delivery is usually performed through target-controlled infusion (TCI) systems whose algorithms rely on pharmacokinetic and pharmacodynamic models. This work presents statistical models to estimate both the infusion rate and the bolus administration. The modeling strategy relies on multivariate linear models, based on patient characteristics such as age, height, weight and gender along with the desired target concentration. A clinical database collected with a RugLoopII device on 84 patients undergoing ultrasonographic endoscopy under sedation-analgesia with propofol and remifentanil is used to estimate the models (training set with 74 cases) and assess their performance (test set with 10 cases). The results obtained in the test set comprising a broad range of characteristics are satisfactory since the models are able to predict bolus, infusion rates and the effect-site concentrations comparable to those of TCI. Furthermore, comparisons of the effect-site concentrations for dosages predicted by the proposed Linear model and the Marsh model for the same target concentration is achieved using Schnider model and a factorial design on the factors (patients characteristics). The results indicate that the Linear model predicts a dosage profile that is faster in leading to an effect-site concentration closer to the desired target concentration.

Abstract
Dysfunctions of the autonomic nervous system in critically ill patients with Acute Brain Injury (ABI) lead to changes in Heart Rate Variability (HRV) which appear to be particularly marked in patients subsequently declared in Brain Death (BD). HRV series are non-stationary, exhibit long memory in the mean and time-varying conditional variance (volatility), characteristics that are well modeled by AutoRegressive Fractionally Integrated Moving Average (ARFIMA) models with Generalized AutoRegressive Conditional Heteroscedastic (GARCH) errors. The long memory is estimated by the parameter d of the ARFIMA-GARCH model, whilst the time-varying conditional variance parameters, u and v characterize, respectively, the short-range and the persistence in the conditional variance. In this work, the ARFIMA-GARCH approach is applied to HRV series of 15 pediatric patients with ABI admitted in a pediatric intensive care unit, 5 of which has BD confirmed and 9 patients survived. The long memory and time-varying conditional variance parameters estimated by ARFIMA-GARCH modeling significantly differ between groups and seem able to contribute to characterize disease severity in children with ABI.

Abstract
This paper introduces new classes of bivariate time series models being useful to fit count data time series with a finite range of counts.. Motivation comes mainly from the comparison of schemes for monitoring tourism demand, stock data, production and environmental processes. All models are based on the bivariate binomial distribution of Type II. First, a new family of bivariate integer-valued GARCH models is proposed. Then, a new bivariate thinning operation is introduced and explained in detail. The new thinning operation has a number of advantages including the fact that marginally it behaves as the usual binomial thinning operation and also that allows for both positive and negative cross-correlations. Based upon this new thinning operation, a bivariate extension of the binomial autoregressive model of order one is introduced. Basic probabilistic and statistical properties of the model are discussed. Parameter estimation and forecasting are also covered. The performance of these models is illustrated through an empirical application to a set of rainy days time series collected from 2000 up to 2010 in the German cities of Bremen and Cuxhaven.